Macrophages play a central role in the pathogenesis of atherosclerosis. Our previous study demonstrated that solute carrier family 37 member 2 (SLC37A2), an endoplasmic reticulum-anchored phosphate-linked glucose-6-phosphate transporter, negatively regulates macrophage Toll-like receptor activation by fine-tuning glycolytic reprogramming in vitro. Whether macrophage SLC37A2 impacts in vivo macrophage inflammation and atherosclerosis under hyperlipidemic conditions is unknown. We generated hematopoietic cell-specific SLC37A2 knockout and control mice in C57Bl/6 Ldlr^-/- mice by bone marrow transplantation. Hematopoietic-specific SLC37A2 deletion in Ldlr^-/- mice increased plasma lipid concentrations 12-16 wks of Western diet induction, attenuated macrophage anti-inflammatory responses, and resulted in more atherosclerosis compared to Ldlr^-/- mice transplanted with wild type bone marrow. Aortic root intimal area was inversely correlated with plasma IL-10 levels, but not total cholesterol concentrations, suggesting inflammation but not plasma cholesterol was responsible for increased atherosclerosis in bone marrow SLC37A2-deficient mice. Our in vitro study demonstrated that SLC37A2 deficiency impaired IL-4-induced macrophage activation, independently of glycolysis or mitochondrial respiration. Importantly, SLC37A2 deficiency impaired apoptotic cell-induced glycolysis, subsequently attenuating IL-10 production. Our study suggests that SLC37A2 expression is required to support alternative macrophage activation in vitro and in vivo. In vivo disruption of hematopoietic SLC37A2 accelerates atherosclerosis under hyperlipidemic pro-atherogenic conditions.

中文翻译：

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造血-SLC37A2缺陷加速LDL受体缺陷小鼠的动脉粥样硬化

巨噬细胞在动脉粥样硬化的发病机制中起着核心作用。我们之前的研究表明，溶质载体家族 37 成员 2 (SLC37A2)，一种内质网锚定的磷酸盐连接的葡萄糖-6-磷酸转运蛋白，通过在体外微调糖酵解重编程来负调节巨噬细胞 Toll 样受体的激活。巨噬细胞 SLC37A2在高脂血症条件下是否影响体内巨噬细胞炎症和动脉粥样硬化尚不清楚。我们通过骨髓移植在 C57Bl/6 Ldlr ^-/-小鼠中生成了造血细胞特异性 SLC37A2 敲除和对照小鼠。Ldlr 中造血特异性 SLC37A2 缺失^-/-与移植了野生型骨髓的Ldlr ^-/-小鼠相比，小鼠在西方饮食诱导的 12-16 周内增加了血脂浓度，减弱了巨噬细胞的抗炎反应，并导致更多的动脉粥样硬化。主动脉根内膜面积与血浆 IL-10 水平呈负相关，但与总胆固醇浓度呈负相关，这表明炎症而非血浆胆固醇是导致骨髓 SLC37A2 缺陷小鼠动脉粥样硬化增加的原因。我们的体外研究表明，SLC37A2 缺乏会损害 IL-4 诱导的巨噬细胞活化，而与糖酵解或线粒体呼吸无关。重要的是，SLC37A2 缺乏会损害凋亡细胞诱导的糖酵解，随后减弱 IL-10 的产生。我们的研究表明，需要 SLC37A2 表达来支持体外和体内的替代巨噬细胞激活。在高脂血症促动脉粥样硬化条件下，造血 SLC37A2 的体内破坏加速了动脉粥样硬化。